The present invention relates to a test device and method for the colorimetric determination of a chemical or biochemical component (analyte) in interstitial body fluid. In particular the present invention relates to a dry reagent test strip from which an analyte presence and/or concentration is determined by visual interpretation or by the use of an instrument. Such test strips are commonly used for determination of glucose level in blood by diabetics.
In the description of the Background of the present invention that follows, reference is made to ceratin structures and methods, however, such references should not necessarily be construed as an admission that these structures and methods qualify as prior art under the applicable statutory provisions. Applicants reserve the right to demonstrate that any of the referenced subject matter does not constitute prior art with respect to the present invention.
Numerous devices have been developed to test for presence and quantity of analytes in aqueous samples, such as whole blood or urine. The patent and technical literature of the last thirty years is replete with inventions which utilize a reagent strip containing a dry chemistry reagent system. A dry chemistry reagent system is a system in which the wet chemistries are imbibed into an absorbent or bibulous medium, dried, and later reconstituted by fluid from the test sample. The reagent strips contain an indicator which changes color, depending on the presence or concentration of a particular analyte in a biological fluid applied to the strip. These strips may be read visually by reference to a color standard or colorimetrically by an instrument calibrated or programmed to detect a certain color. Although some of these strips use reduction chemistries, more commonly they involve an oxidizable dye or dye couple. Some of the strips include an enzyme, such as glucose oxidase, which is capable of oxidizing glucose to gluconic acid and hydrogen peroxide. They also contain an oxidizable dye and a substance having peroxidative activity, which is capable of selectively catalyzing oxidation of the oxidizable dye in the presence of hydrogen peroxide. (See, for example, U.S. Pat. No. 5,306,623, to Kiser et al.). Examples of these devices, in addition to those used to test blood glucose, include tests for cholesterol, triglycerides, calcium or albumin in whole blood, and for protein, ketones, albumin or glucose in urine.
Dry chemistry reagent strips incorporating enzyme-based compositions are used daily by millions of diabetics to determine blood glucose concentrations. The NIH sponsored study, the Diabetes Complications and Control Trial, demonstrated conclusively that careful control of blood glucose levels can significantly reduce the incidence of serious complications of diabetes such as vision loss and kidney malfunction. Most diabetics must test themselves periodically in order to make appropriate adjustments to their diet or medication. It is thus especially important for diabetics to have rapid, low pain, and accurate reagent strips for glucose determination. The embodiment of dry chemistry reagent systems in test strips enable simple yet effective analytical protocols. However, current blood base devices require the patient to lance their fingers with a lancing device which cause considerable initial and residual pain. This process has caused many patients to reduce the amount of testing they do because of the pain associated with testing.
The technologies embodied in the products which have been developed to date have certain limitations from the perspective of the end user and/or the manufacturer. The issues surrounding sample acquisition and the complexities of measuring in or separating blood are a significant issue for the current technology. The existing technology to acquire a blood sample utilizes fingersticks which hurt. U.S. Pat. No. 5,951,492, entitled "Methods and Apparatus for Sampling and Analyzing Body Fluid", describes a means for painless blood sampling. This system still requires needles and blood and a mechanism or device for blood sampling. Blood is plentiful but hard to read calorimetrically due to red cell presence. There is, therefore, a need to overcome some of the limitations of currently available colormetric testing systems. U.S. Pat. No. 3,092,465, issued to Adams et al., U.S. Pat. No. 3,298,789, issued to Mast and U.S. Pat. No. 3,630,957, issued to Rey et al., all describe a basic reagent system which became a standard for calorimetric determination of glucose in biological samples. These patents describe the formation of a film layer or semi-permeable coating over the bibulous matrix to hold back the larger particulates, such as red blood cells, and allow fluid to permeate into the bibulous matrix. This approach requires the removal of red blood cells by washing or wiping to enable visual inspection or instrument reading of the indication of the dye color formed in the matrix.
U.S. Pat. No. 3,607,093 to Stone, discloses a membrane for testing blood where the membrane has a skin permeable to solutions but impermeable to solids such as red blood cells and to macromolecules such as proteins. This membrane is disclosed as being used by applying a blood sample then wiping away the red blood cells from the skin in order to reach the test indication through the skin.
U.S. Pat. No. 3,552,928, issued to Fetter, discloses the use of certain water soluble salts and amino acids in reagent formulations as separation agents to provide blood separation. With solids such as red blood cells substantially removed from the biological fluid, there is less background color at the test site to obscure a change in coloration produced by a testing reagent.
Phillips et al., U.S. Pat. No. 4,935,346, discloses a system wherein a whole blood sample is applied to the device and indicator development occurs in the presence of the colored components of the sample. Measurements of the color change in indicator are made at two distinct wavelengths to eliminate the interferences from the presence of colored blood components.
Kiser et al., U.S. Pat. Nos. 5,306,623 and 5,418,142, disclose a visual meter device which incorporates various coatings on a matrix material to filter red blood cells from fluids. Similar devices for visual indication are disclosed by Hochstrasser in U.S. Pat. Nos. 3,964,871 and 4,059,407.
Terminello et al., U.S. Pat. No. 4,774,192, disclose a system in which the matrix is formed of an asymmetric material used to filter the red blood cells in the sample. The asymmetric material has a density gradient from one side to the other to progressively separate red blood cells from the fluids.
Daffem et al., U.S. Pat. No. 4,994,238, disclose a test device that comprises an asymmetric reagent layer that has progressively finer filtration with increased distance from one surface toward the other surface.
Castino et al., U.S. Pat. No. 5,456,835, disclose the use of filters formed of ligand modified polymeric film such as polypropylene fibers and polyethersulfone fibers.
Vogel et. al., U.S. Pat. No. 4,477,575, disclose the use of glass fiber material to achieve blood separation through the thickness of the material. Blood is applied to one side of the glass fiber, and relatively clear fluid migrates out of the opposite side. This fluid is delivered to an additional layer where the detection of analytes can occur.
Macho et al., U.S. Pat. No. 5,451,350, disclose the use of absorbent channels to distribute sample fluid in multi-zone test devices. Charlton et al., U.S. Pat. No. 5,208,163, also disclose the use of capillary channels to distribute blood to various chambers in the device.
In order to avoid the pain and/or complexity of measuring in whole blood, some people have sought to access interstitial fluid. The professed advantages are painlessness and bloodlessness (consumer and measurement system advantages). Many of these approaches leverage approaches designed to deliver drugs to the interstitial space in lieu of needle injections or other means of drug delivery. Others have pursued noninvasive approaches to analyte measurement.
Gerstel et al., U.S. Pat. No. 3,964,482, disclose the use of a drug delivery device for precutaneous administration of a drug comprising of a plurality of projections.
Japanese Patent No. JP 2551743-B2 assigned to Sansei Denki KK describes a skin damage forming device for medicine delivery. This device causes small holes formed by tiny needles in the device.
Fendrock, U.S. Pat. No. 5,305,746, describes a patch for reducing skin impedance by using an array of flexible tines.
Whitney et al., U.S. Pat. No. 4,235,234, discloses a subcutaneous injection system which uses projections to inject a drug into the tissue.
Azimi, World Patent WO 95/02357, discloses a noninvasive glucose monitor that does not rely on heat, electricity or chemicals to collect glucose from interstitial fluid across a patient's skin.
Liplovker, U.S. Pat. No. 5,617,851, discloses a noninvasive method and apparatus for withdrawing fluid from an organism and determining the concentration of a substance in the fluid.
Liplovker, U.S. Pat. No. 5,421,816, discloses a method of using ultrasound to move a drug across the skin of a patient.
Halili et al., U.S. Pat. No. 5,586,553, discloses a transcutaneous sensor placed at a selected site within a patient's body to determine the concentration of analyte in a patient.
Eppstein et al., U.S. Pat. No. 5,458,140, discloses a method of enhancing the permeability of the skin using ultrasound either in the presence or absence of chemical skin permeation enhancers to permit analytes to cross the skin to an analyte collection site.
Schroeder et al., U.S. Pat. No. 5,140,985, discloses a device which measures the blood glucose of a patient via the concentration of glucose in sweat.
Stanley et al., U.S. Pat. No. 5,139,023, disclose an apparatus and method for noninvasive blood glucose monitoring by correlation with amount of glucose which permeates an epithelial membrane. The glucose receiving medium includes a glucose permeation enhancer capable of increasing the permeability of glucose across the epithelial membrane.
The disclosures of the above-discussed documents are incorporated herein by reference. The devices and methods discussed above provide varying degrees of effectiveness of blood analysis at varying degrees of complexity and pain.
It is an object of the present invention to provide improved devices and methods to improve the performance and minimize the pain and complexity compared to the prior art devices.
It is a further object of the present invention to provide a fully disposable, discrete reading system for detecting analyte presence or concentration.
It is another object of this invention to provide a dry reagent chemistry system capable of analyzing body fluids for one or more analytes without finger lancing.
It is another object of this invention to provide a means for performing microtitration for the analysis of body fluid in a system which enables the ready visual determination of analyte presence or concentration.
The above objects as well as others are achieved by the devices, methods and systems of this invention as disclosed herein.